The research proposed in this application is to identify a novel drug candidate for the treatment of Alzheimer's disease (AD). AD is the largest neurodegenerative disease, afflicting ~4.5 million Americans and having total societal costs associated with the disease of about $100 billion per year. Incidence and costs of this disease are projected to grow substantially in the coming decades and there is no currently approved therapy that is truly effective. Current therapies are considered to be palliative, directed towards disease symptoms, and their efficacy is typically of limited duration, slowing the progression of the disease by several months. In this project, we will identify the active component of a botanical extract that has been shown to selectively lower the concentration of amyloid beta peptide 1-42 (AB42, "long A-beta"). Deposition of AB42 is an early and ubiquitous feature of AD. AB42 is less soluble and more toxic than the primary form of AB, the 2 residue shorter form AB40. Genetic mutations in the precursor protein of Ap, and in the enzymes that process it to produce Ap, that are associated with early-onset AD increase AB42 levels. Lowering AB42 selectively is expected to substantially lower the amyloid-forming potential of the total Ap pool, slow the growth of amyloid deposits, retard the transformation of diffuse amyloid plaques to the compact dense senile amyloid plaques associated with disease, and inhibit the formation of toxic oligomers of Ap associated with acute toxicity to neurons. The AB42 lowering activity of interest in this proposal is derived from the flowering plant actaea racemosa. This plant, also known as black cohosh, is the source of an extract that is widely used as a nutriceutical for the treatment of menopausal symptoms in women. Preliminary data suggest that the AB42 lowering activity is separate from the triterpenes associated with the conventional use of this extract. In phase 1 of this project, we will use cell-based assays of AB40/42 expression to guide fractionation of actaea racemosa extract and isolate substantially enriched samples of the AB42 lowering activity. In phase 2 of this project, the active component of the extract will be purified to homogeneity, its structure will be determined and preliminary efficacy and pharmacology studies will be performed in mice. This compound will be of interest for other neurological disorders where Ap-related toxicity may be a contributing factor. [unreadable] [unreadable]